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Psychedelics in Psychiatry–Keeping the Renaissance From Going Off the Rails

December 2020
JAMA Psychiatry online

DOI:10.1001/jamapsychiatry.2020.3672

Authors:

David Bryce Yaden

Johns Hopkins Medicine

Roland R Griffiths

Johns Hopkins Medicine

There is a resurgence, some say renaissance, of clinical research on psychedelic substances after decades of dormancy. Recent studies have produced findings suggesting psychedelics may demonstrate substantial efficacy for serious psychiatric conditions such as mood and substance use disorders. As a result, ongoing clinical trials with the psychedelic psilocybin have been given the Breakthrough Therapy designation by the US Food and Drug Administration that could result in medical approval for major depressive disorder and/or treatment-resistant depression.

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Psychedelics in Psychiatry—Keeping the Renaissance From

Going Off the Rails

There is a resurgence, some say renaissance, of clini-

cal research on psychedelic substances after decades of

dormancy. Recentstudies have produced findings sug-

gesting psychedelics may demonstrate substantial effi-

cacy for serious psychiatric conditions such as mood and

substance use disorders. As a result, ongoing clinical trials

with the psychedelic psilocybin have been given the

Breakthrough Therapy designation by the US Food and

Drug Administration that could result in medical ap-

proval for major depressive disorder and/ortreatment-

resistant depression.

This new period of psychedelic research, ongoing

since at least 2006, has now lasted for about the same

length of time as psychedelic research in the 1950s and

1960s did before it ground to a halt. As contemporary

psychedelic research results accrue, the field may be fac-

ing a fork in the road to clinical applications. One path

forward allows for the same kinds of exuberance, uto-

pian thinking, and uneven clinical approaches that con-

tributed to ending the previous period of research. Com-

bined with the contemporary tendency to politicize

science, the possibility of a repeat of the 1960s repre-

sents a significant concern. Another path forward, a more

careful and systematic one, involves the appropriate in-

tegration of psychedelic treatments into existing evi-

dence-based psychiatric paradigms such as psycho-

therapy and pharmacotherapy.

This Viewpoint offers perspectives on how the psy-

chedelic research renaissance can stay on the path that

leads to the integration of these medications into the

standard of care rather than recapitulating the ethical and

sociopolitical problems that led to the previous period

of research going off the rails.

History of Psychedelic Research

Psilocybin is a psychedelic compound in certain mush-

rooms, which have been used in sacred ceremonies

among indigenous peoples in Mexico and elsewhere for

centuries. Other psychedelic compounds, such as mes-

caline and DMT (N,N-dimethyltryptamine), have like-

wise been used for hundreds or thousands of years in

ritual contexts. The psychedelic LSD (lysergic acid di-

ethylamide), which the Swiss chemist Albert Hofmann

synthesized in 1938, led to innovations in understand-

ing serotonin pharmacology and, eventually (albeit in-

directly), to the development of therapeutics that modu-

late serotonin function such as selective serotonin

reuptake inhibitors.

During a period in the 1950s and 1960s, research es-

tablished that psychedelic substances produce substan-

tially altered states of consciousness. This era of re-

search showed psychedelics as having considerable

promise in the treatment of depression in patients with

cancer and alcohol use disorder. However, in the late

1960s, clinical research on psychedelics was function-

ally prohibited because of burdensome governmental

regulations, the perceived association of the sub-

stances with an anti-establishment counterculture, mis-

perception of risk resulting from negatively biased me-

dia coverage, and lapses in research ethics.

Recent Research

After several decades of inactivity in the US, psyche-

delic research in healthy psychedelic-naive partici-

pants was restarted at Johns Hopkins in 2000. Studies

have focused on the serotonergic psychedelics (espe-

cially psilocybin), so called because these compounds

function as partial 5-HT

serotonin receptor agonists.

Many studies have confirmed the low toxicity and mini-

mal addiction potential of serotonergic and other

psychedelics.

The study most often cited as restarting the cur-

rent period of psychedelic research was a double-blind

randomized clinical trial that examined psilocybin ad-

ministered in a supportive setting. The intervention re-

sulted in long-term increases in positive mood, life sat-

isfaction, and prosocial behavior in healthy participants.

Two double-blind randomized clinical trials on patients

with life-threatening cancer diagnoses showed sus-

tained decreases in anxiety and depression.

3,4

Addi-

tional research in clinical populations has suggested ef-

ficacy for treatment of mood disorders and substance

use disorders.

5-7

These and other recent and ongoing

studies suggest the potential for psychedelics to be used

as new and effective treatments for a range of psychi-

atric conditions.

Dead Ends

Despite this promise, cultural forces such as those that

occurred in the 1960s may threaten contemporary re-

search progress and the clinical application of psyche-

delics. For example, numerous recent popular press

books, websites, podcasts, and media reports have un-

critically promoted presumed benefits of psychedelics.

Patient demand is growing, as is interest in the general

population, with the possibility that expectations are out-

pacing the current data on what outcomes can be con-

fidently foreseen. Psychedelics are neither a cure for

mental disorders nor a quick fix for an unfulfilled life and

should not be portrayed as a panacea. Ominously, pro-

psychedelic subcultures are increasingly fostering uto-

pian visions for society based on research findings that,

while intriguing, still must be considered preliminary.

If psychedelic research is going to avoid another pe-

riod of prohibition, we must learn from the lessons of the

past. It is critically important that the medical and sci-

VIEWPOINT

David B. Yaden,PhD

Department of

Psychiatry and

Behavioral Sciences,

Johns Hopkins

University School of

Medicine, Baltimore,

Maryland; and Center

for Psychedelic and

Consciousness

Research, Johns

Hopkins University

School of Medicine,

Baltimore, Maryland.

Mary E. Yaden,MD

Department of

Psychiatry,Perelman

School of Medicine,

University of

Pennsylvania,

Philadelphia.

Roland R. Griffiths,

PhD

Department of

Psychiatry and

Behavioral Sciences,

Johns Hopkins

University School of

Medicine, Baltimore,

Maryland; and Center

for Psychedelic and

Consciousness

Research, Johns

Hopkins University

School of Medicine,

Baltimore, Maryland.

Corresponding

Author: Roland R.

Griffiths, PhD,

Psychiatry,Johns

Hopkins Center for

Psychedelic and

Consciousness

Research, 5510 Nathan

Shock Dr, Baltimore,

MD 21224 (rgriff@jhmi.

edu).

Opinion

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entific communities be vigilant in opposing the conflation of sci-

ence with larger cultural agendas, as occurred in the 1960s with the

blending of psychedelics into the antiwar and other anti-

establishment movements. The enthusiasms that attend such agen-

das should not be allowed to supersede the scientific and regula-

tory processes meant to carefully vet these substances and their

application in a variety of mood and behavioral disorders.

A Way Forward

More randomized clinical trials are necessary to replicate and ex-

tend the promising findings of open-label trials and to better un-

derstand contraindications and other potential risks. Furthermore,

additional studies will be required to better understand the mecha-

nisms by which psychedelics exert their therapeutic effects, ideal

dosing schedules, selection of the most effective compounds, and

optimal clinical management. The lure of the approval of the clini-

cal use of psychedelics raises the possibility that a vast arrayof eclec-

tic and untested psychotherapeutic techniques may be applied in

conjunction with medication administration. Considering that psy-

chedelic experiences are known to be strongly influenced by expec-

tations and the context (ie, set and setting) and that such experi-

ences sometimes result in major shifts in worldview, adding

psychedelics to fringe or unproven psychotherapeutic paradigms

may increase the risk of iatrogenic harm. The safest and most effec-

tive psychedelic treatment protocols will likely be those that inte-

grate existing evidence-based interventions and psychotherapies.

Conclusions

Psychiatric treatments have seen only modest innovation for de-

cades. Research on psychedelics is pointing to the potential for new

treatment options for a variety of psychiatric conditions. However,

as testing and clinical applications expand, it is still possible for re-

searchers and clinicians to squander this opportunity.The word re-

naissance comes from the French wordfor rebir th; however, this may

be somewhat of a misnomer as it has been more than 2 decades since

clinical psychedelic research resumed in the US. We believethis new

era of psychedelic research is no longer being reborn but rather com-

ing into maturity. Whether this era of psychedelic research will con-

clude with another scientific and clinical dead-end period of prohi-

bition or move ahead into a productive time of mainstream research

and clinical application remains to be seen. We owe it to the next

generation of researchers and clinicians, and to the millions of pa-

tients with mood and substance use disorders who may benefit from

these treatments, to ensure that no exceptions be made in the stan-

dards of research or clinical application for psychedelics, regard-

less of their seemingly exceptional potential.

ARTICLE INFORMATION

Published Online: December 2, 2020.

doi:10.1001/jamapsychiatry.2020.3672

Conflict of Interest Disclosures: Dr Griffiths

reports grants from the Steven and Alexandra

Cohen Foundation and from Tim Ferris, Matt

Mullenweg, Blake Mycoskie, and Craig Nerenberg

for funding the Johns Hopkins Center for

Psychedelic and Consciousness Research (CPCR)

during the conduct of the study; grants from the

Riverstyx Foundation, a crowdsourced funding

campaign organized by Tim Ferriss, and National

Institute on Drug Abuse (grant R01DA03889) for

research support outside the submitted work;

personal fees from the Heffter Research Institute

(HRI) to cover travel costs as member of the board

of directors of HRI outside the submitted work; and

is site principal investigator for a multisite trial of

psilocybin-facilitated treatment of major depressive

disorder, which is sponsored by the Usona Institute.

No other disclosures were reported.

Funding/Support: Support for Drs D. Yadenand

Griffiths through the Johns Hopkins Center for

Psychedelic and Consciousness Research was

provided by Tim Ferriss, Matt Mullenweg, Blake

Mycoskie, Craig Nerenberg, and the Steven and

Alexandra Cohen Foundation. Dr M. Yaden was

supported by the National Institute of Mental

Health (grant R25MH119043).

Role of the Funder/Sponsor:The funders had no

role in the design and conduct of the study;

collection, management, analysis, and

interpretation of the data; preparation, review, or

approval of the manuscript; and decision to submit

the manuscript for publication.

Additional Contributions: We thank James B.

Potash, MD (Department of Psychiatry and

Behavioral Sciences, Johns Hopkins University

School of Medicine), for his helpful comments and

suggestions. He was not compensated.

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Opinion Viewpoint

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Psychedelics

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PHARMACOL REV

David Nichols

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybinassisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level–dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network. © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study

Article

Full-text available

Jan 2015
J PSYCHOPHARMACOL

Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms. NCT02061293. © The Author(s) 2015.

Pilot Study of the 5-HT2AR Agonist Psilocybin in the Treatment of Tobacco Addiction

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Sep 2014
J PSYCHOPHARMACOL

Despite suggestive early findings on the therapeutic use of hallucinogens in the treatment of substance use disorders, rigorous follow-up has not been conducted. To determine the safety and feasibility of psilocybin as an adjunct to tobacco smoking cessation treatment we conducted an open-label pilot study administering moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin within a structured 15-week smoking cessation treatment protocol. Participants were 15 psychiatrically healthy nicotine-dependent smokers (10 males; mean age of 51 years), with a mean of six previous lifetime quit attempts, and smoking a mean of 19 cigarettes per day for a mean of 31 years at intake. Biomarkers assessing smoking status, and self-report measures of smoking behavior demonstrated that 12 of 15 participants (80%) showed seven-day point prevalence abstinence at 6-month follow-up. The observed smoking cessation rate substantially exceeds rates commonly reported for other behavioral and/or pharmacological therapies (typically <35%). Although the open-label design does not allow for definitive conclusions regarding the efficacy of psilocybin, these findings suggest psilocybin may be a potentially efficacious adjunct to current smoking cessation treatment models. The present study illustrates a framework for future research on the efficacy and mechanisms of hallucinogen-facilitated treatment of addiction.

Psilocybin Can Occasion Mystical-Type Experiences Having Substantial and Sustained Personal Meaning and Spiritual Significance

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Aug 2006

Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions. The participants were hallucinogen-naïve adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers' behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer's attitudes and behavior. Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers. When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.